Translational research, bringing new laboratory findings quickly to improve prevention, treatment, quality of life, and survival for breast cancer patients, has been the focus of the team now forming the Baylor Breast Center for over 25 years. During the first years of our SPORE, our tumor bank which made much of this rapid translation possible became a national resource, while basic cell and molecular biology research suggested new clinical implications for endocrine and chemotherapy resistance, breast cancer prevention, metastasis, and development of premalignant lesions. Developmental projects ranged even further in seeking new translational possibilities. In this SPORE renewal, we build on the results developed in our earlier work and on new findings and new technologies, in five projects and several supporting components. (1) Targeting HER2 with agents such as trastuzumab has become an important treatment, but resistance often develops. We will explore and take to clinical trials our promising preclinical evidence that more complete blockade of the complex HER network or of its cross-talk with the estrogen receptor may overcome this resistance. (2) Based on our data suggesting that a small subpopulation of resistant tumor cells with stem-cell-like properties may be the source of tumor re-growth after apparently successful chemotherapy, we will investigate this potential cancer stem cell population and begin trials of treatments targeting these cells along with the more numerous, more differentiated tumor cells for more complete and enduring responses. (3) Prevention trials have shown that SERMs like tamoxifen or raloxifene can greatly reduce ER-positive but not ER-negative breast cancer in high-risk women. Now we will apply our prevention experience with RXR agonists such as bexarotene to develop preclinical and clinical combinations with SERMs to prevent both ER-positive and ER-negative breast cancer. (4) Surprising new clinical and laboratory data suggests that overexpression of the androgen receptor may be an important cause of resistance to endocrine therapy with either tamoxifen or aromatase inhibitors. We will seek the mechanisms behind this interaction, and will initiate a clinical trial designed to reverse this resistance with an already-approved AR antagonist. (5) The IGF pathway has been shown to be important in breast cancer development and progression, but therapeutic targeting is complicated by high cross-reactivity with the insulin receptor. We will investigate the efficacy of a new, specific IGF-I receptor antibody and explore strategies to lessen toxicities associated with collateral insulin receptor blockade by other IGF pathway targeting approaches. Though parts of our unique breast Tissue Resource were lost in the floods of 2001, much remains, and new accessions are further enhancing this critical resource. Biostatistics, Pathology, and Administrative Cores also1 give key support to this SPORE. Our highly successful Developmental Projects and Career Development programs will continue to encourage new ideas and new investigators in translational breast cancer research. Our new Dan L. Duncan Cancer Center provides valuable direct support and collaboration for this SPORE effort.